Malaria Parasite Development, Drug Resistance, Pathogenesis, and Genomics

2016-2017年间，我们利用约氏疟原虫/小鼠模型，重点研究了疟疾发病的分子机制和信号转导途径。 我们在几个项目上取得了良好的进展： 1.我们完成了一个研究CD40在疟疾感染过程中调节I型干扰素(IFN-I)反应的作用的项目。我们发现CD40能增强刺激性干扰素-I的应答，并在寄生虫血症控制和宿主存活中发挥作用。我们还发现，寄生物质如DNA和RNA可以通过TLR信号通路刺激CD40的表达。这项研究揭示了CD40在先天干扰素-I反应中的未知功能，并为更好地理解和管理疟疾提供了重要信息。这项研究发表在《公共科学图书馆·病原体》杂志上。 2.我们还完成了寄生虫E3泛素连接酶调控寄生虫生长和疾病毒力的功能验证。我们用CRISPR/Cas9方法替换了E3泛素Liagse基因的部分编码序列。在部分基因序列交换后，我们发现寄生虫生长发生了变化，证实了该基因在寄生虫发育和疾病毒力中的作用。一份手稿已被《自然通讯》接受。 3.继续研究约氏疟原虫感染后炎症反应的分子机制。我们现在专注于由干扰素-γ介导的促炎反应，并正在剖析寄生虫感染后导致炎症的分子相互作用和细胞类型。一份手稿已经提交给科学报告。 4.我们在其他项目上取得了良好的进展，包括一种名为March1的基因。我们发现该基因可以调节宿主对多种寄生虫株的感染反应。我们正在研究该基因如何调节宿主免疫反应的分子机制。 5.此外，我们与休斯敦卫理公会研究所的科学家合作，确定了pDC中干扰素-I信号的关键调控机制，以及免疫细胞在产生对致命疟疾感染的有效免疫中的特定阶段功能，发表在《免疫》杂志上。 6.在第二个合作项目中，我们发现了转录因子FOSL1在调节干扰素-I反应中的一个以前未知的作用。我们发现FOSL1可以通过阻断TBK1和TRAF3/TRIF的相互作用来抑制干扰素-I对疟疾和病毒感染的反应。这项研究发表在mBio上。 7.我们与宾夕法尼亚州立大学的科学家合作，利用全基因组关联分析，确定了中国-缅甸边境采集的恶性疟原虫对多种抗疟疾药物的抗性相关遗传位点。这项研究发表在《科学报告》上。 8.我们与厦门大学的科学家合作，继续研究了中国南部地区鸟类寄生虫(白细胞体)的流行情况。我们还测试了几种三环化合物对寄生虫配子体的抑制作用。这项研究发表在《公共科学图书馆·综合》上。 9.在第二个合作项目中，我们开发了一种CRISPR/Cas9方法，允许对约氏疟原虫基因进行顺序编辑，该方法发表在《分子和生化寄生虫学》杂志上。

During the year of 2016-2017, we focused on studying molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii/mouse model. We have made good progresses in several projects: 1. We finished a project studying the role of CD40 in regulating type I interferon (IFN-I) response during malaria infection. We showed that CD40 could enhance STING-stimulated IFN-I response and played a role in parasitemia control and host survival. We also showed that parasite materials such as DNA and RNA could stimulate CD40 expression through TLR signaling pathways. This study reveals a previously unrecognized function of CD40 in innate IFN-I responses and provides important information for better understanding and management of malaria. This work was published in PLoS Pathogens. 2. We have also finished functional verification of a parasite E3 ubiquitin ligase in regulating parasite growth and disease virulence. We replaced partial coding sequences of the E3 ubiquitin liagse gene using the CRISPR/cas9 method. We showed changed parasite growth after exchange of partial gene sequences, which confirms a role of the gene in parasite development and disease virulence. A manuscript has been accepted by Nature Communications. 3. We continued to study the molecular mechanism of inflammatory responses after P. yoelii infection. We are now focusing on pro-inflammatory responses mediated by IFN-gamma and are dissecting the molecular interactions and cell types contributing to inflammation after parasite infection. A manuscript has been submitted to Scientific Reports. 4. We have made good progresses on other projects, including a gene called March1. We found that this gene can regulate host response to infections of multiple parasite strains. We are investigating the molecular mechanism of how this gene regulates host immune response. 5. Additionally, in collaboration with scientists at Houston Methodist Research Institute, Houston, we have identified a critical regulatory mechanism of IFN-I signaling in pDCs and stage-specific function of immune cells in generating potent immunity against a lethal malaria infection, which was published in Immunity. 6. In a second collaborative project, we discovered a previously unknown role of the transcription factor FOSL1 in regulating IFN-I response. We showed that FOSL1 could inhibit IFN-I responses to malaria and viral infections by blocking TBK1 and TRAF3/TRIF Interactions. This work was published in mBio. 7. In collaboration with scientists at Penn State University, we used genome-wide association analysis to identify genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum parasites collected from China-Myanmar border. This work was published in Scientific Reports. 8. In collaboration with scientists at Xiamen University, we continued to study prevalence of a bird parasite (Leucocytozoon sabrazesi) in Southern China. We also tested several tricyclic compounds against the gametocyte of the parasite. The work was published in PLoS ONE. 9. In a second collaborative project, we developed a CRISPR/Cas9 method that allows sequential editing of Plasmodium yoelii genes, which was published in Molecular and Biochemical Parasitology.